Antimicrobial Therapy: Intro

Question 1

Antimicrobial Minimum Inhibitory Concentration

Answer 1

• Minimum inhibitory Concentration (MIC)
• Lowest concentration of antimicrobial needed to inhibit visible microbial growth
• Estimates susceptibility of specific bacteria to antimicrobials

Question 2

MIC results

Answer 2

• Reported as:
  
  • Susceptible: reasonable likelihood of success
  • Intermediate: increases in dose may result in success or highly susceptible location in body
  • Resistant: unlikely to result in clinical success
• Factors affecting susceptibility breakpoints
  
  • animal species
  • Bacteria
  • Disease
  • Drug
  • Dose
  • Route
  • Frequency

Question 3

Spectrum

Answer 3

The bacteria typically susceptible to an antimicrobial

Question 4

Resistance:

Intrinsic

Answer 4

the bacteria were never susceptible to the antimicrobial

Question 5

Resistance:

Acquired

Answer 5

at some point the bacteria were susceptible to the antimicrobial

Question 6

Resistance

Answer 6

• We do NOT “cause” resistant mechanisms, we select for them
• The mechanisms are already often in the bacterial population or occur through spontaneous mutation independent of antimicrobial treatment
  
  • when susceptible die off, the resistant strains are left and flourish
• Mechanisms of resistnace include:
  
  • efflux pumps or decreased uptake
  • inactivation of the antibiotic
  • modify the target
• Resistance mechanisms may be shared within bacterial species or between bacterial species

Question 7

Treatment Goals:

Therapeutic

Answer 7

clear the infection

Question 8

Treathment Goals:

Prophylaxis / Prevention

Answer 8

Treating prior to bacterial exposure to prevent infection

Question 9

Treatment Goals:

Growth Promotion

Answer 9

feeding antimicrobials decreases subclinical disease or alters microbiome resulting in more efficient feed conversions

Question 10

Treatment Goal:

Do we need to treat?

Answer 10

• is there a benefit to treatment?
• Is there even an infection?
• A fever may not be due to an infection. It could be inflammation, hyperthermia
• Avoid/minimize adverse effects
• Avoid bacterial resistance selection
• Avoid violative residues in food animals
• Ensure client compliance

Question 11

Bactericidal

Answer 11

antimicrobial kills bacteria

beta lactams, aminoglycosides, nirtoimidazoles, fluoroquinolones

Question 12

Bacteriostatic

Answer 12

inhibit microbial growth

Tetracyclines, macrolides / lincosamides, sulfonamides, -phenicols

Question 13

Pharmacodynamics - What is our target?

Peak / concentration dependent (CMAX:MIC)

Answer 13

• fluroquinolones, aminoglycosides, metronidazole
• Rate/extent of killing increase with increasing concnetrations, then plateaus at about 10X MIC
• Post-antibiotic Effect (PAE):
  
  • continued bacterial death / inhibition due to bacterial damage

Question 14

Pharmacodynamics - What is our target?

Time above MIC (T>MIC)

Answer 14

• Beta Lactams, sulfas, -phenicols
• More important to maintain concentrations above MIC, but no major advantage to markedly exceeeding the MIC

Question 15

Pharmacodynamics - What is our target?

AUC:MIC

Answer 15

• Tetracyclines, macrolides/lincosamides, fluorquinolones
• Total drug exposure over time

Question 16

Pharmacokinetics - effect of dividing a total daily dose

Answer 16

• CMAX higher for once daily administration
  
  • CMAX = 140 mcg/ml given every 24 hours
  • CMAX = 70 mcg/ml given every 12 hours
  • Important for concentration dependent
  • Not so important for time dependent
• CMIN is lowe for once daily administration
  
  • CMIN = 0.05 mcg/ml given every 24 hours
  • CMIN = 1.5 mcg/ml given every 12 hours
  • More dificult to maintian T > MIC
  • Drug free interval decreases aminoglycoside renal toxicity
• AUC
  
  • typically the same for either dosage

Question 17

Routes of Administration:

Oral

Answer 17

• “Ease” of administration, typical lower cost, may increase GI adverse effects
• Fluoroquinolones, Macrolides / lincosamides, metronidazole, TMs
• Some: Beta lactams, -phenicols, tetracyclines

Question 18

Routes of Administration:

Parenteral (IV, IM, SQ)

Answer 18

• May provide more consistent and higher concentrations than PO
• May increase client compliance
• Route for drugs with low bioavailability
  
  • poor lipophilicity
  • First pass metabolism
  • Unstable in GIT
• Aminoglycosides, also same FQs, macrolides, -phenicols, tetracyclines

Question 19

Routes of Administration:

Topical

Answer 19

• Higher concentrations at site of infection
  
  • may enhance spectrum
• Less systemic adverse effects
• Drugs that are toxic systemically, may be applied topically

Question 20

Routes of Elimination:

Metabolism

Answer 20

Hypically inactivates Macrolides, -phenicols

Question 21

Routes of Elimination:

Biliary Secretion

Answer 21

may be active drug or inactive metabolite

Doxycycline

Question 22

Routes of Elimination:

Renal Elimination

Answer 22

May result in high concentrations in the urine and increase efficacy for UTIs

Beta-lactams, aminoglycosides, trimethoprim, some tetracyclines, some fluoroquinolones

Question 23

Drug penetration into protected tissues

Answer 23

CNS, prostate, eye, bronchi

• Limitaitons include:
  
  • lipophilicity
  • protein binding
  • efflux transporters
• In general:
  
  • fluoroquinolones
  • -phenicols
  • Trimethoprim / sulfonamide
  • Some macrolides
  • Some tetracyclines
  • Some cephalosporins penetrate CNS/Prostate/Eye/ well
    
    • cephalexin

Question 24

Species Differences:

Horses

Answer 24

Many antimicrobials disrupt GIT flora, resulting in overgrwoth of pathogenic/opportunistic bacteria = sepsis and death

Many antimicrobials also have poor oral bioavailability

Conversely IV doxycycline is lethal, but can be administered PO

Question 25

Species Differences: cattle

Answer 25

Drug residues, compliance, resistance

Question 26

Species Differences: Dogs

Answer 26

Sulfonamides - autoimmune like reactions, KCS

Question 27

Species Differences: Cats

Answer 27

Fluoroquinolone retinal degeneration Doxycycline, clindamycin esophageal stricture

Question 28

Banned Drugs (Food Animal)

Answer 28

* Extralabel use prohibited: * chloramphenicol - no label * Nitroimidazoles - no label * Fluoroquinolones * Nitrofurazones - no label * Glycopeptides - some label use * Sulfonamides in lactating dairy cows over 20 months of age * Cephalosporins - extralabel doses/routes prohibited, but therapeutic applications in unlaneled diseases OK * applies to major species * Minor species ELDU allowed, cephapirin intrammamary is an exception

Question 29

Limitations of use: Treatment Failure?

Answer 29

* Misdiagnosis * incorrect dose / route / frequency * Immunosuppression * Compliance * Underlying disease * Foreign body / implant / nidus * Pharmacokinetic interaction * True antimicrobial resistance * Reinfection vs. Failure

Question 30

Limitations of Use: Abscesses

Answer 30

antimicrobials are unlikely to be effective without drainage Inability to penetrate and remain active at necessary concentrations

Question 31

Limitations of use: Pseudomonas spp.

Answer 31

* Most Pseudomonas are difficult to treat. If possible use topical * PO effectively limited to Fluoroquinolones * Ceftazidime, carbapenems, anti-pseudomonal penicillins, aminoglycosides

Question 32

Limitations of Use: Enterococcus spp.

Answer 32

* Amoxicillin \>\>\> Tetracylines, chloramphenicols, rifampin, fluoroquinolones, nitrofurantoin * Regardless of susceptibility testing, chephalosporins, trimethoprim sulfa, clindamycin, aminoglycosides, azithromycin are ineffective * If resistant and a co-infection with Enterococcus, sometimes treating the other pathogens will result in clearance of Enterococcus spp.